1,n6-etheno-5-adenosine carboxylates

ABSTRACT

ESTERS OF 1,N6-ETHENO-5&#39;&#39;-ADENOSINE CARBOXYLIC ACID REPRESENTED BY THE FORMULA   3-(2-(R1O-CO-),3-(R2O-),4-(R3O-)-TETRAHYDROFUR-5-YL)-3H-   IMIDAZO(2,1-I)PURINE   WHEREIN R1 IS LOWERALKYL, LOWERALKENYL, LOWERALKYNYL OR CYCLOALKYL; AND R2 AND R3 EACH ARE HYDROGEN OR ACYL, OR R2 AND R3 TAKEN TOGERTHER FORM AN ISOPROPYLIDENE OR BENZYLIDENE MOIETY; AND THE PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF. THE COMPOUNDS WHEREIN R2 AND R3 ARE HYDROGEN ARE USEFUL IN TREATING CARDIOVSCULAR DISORDERS AND ARE PARTICULARLY USEFUL AS ANTI-AGAINAL AND ANTI-HYPERTENSIVE AGENTS. COMPOUNDS WHEREIN R2 AND R3 ARE ACYL OR WHEN TAKEN TOGETHER FORM AN ISOPROPYLIDENE OR BENZYLIDENE MOIETY ARE INTERMEDIATES USEFUL IN THE PREPARATION OF THE FINAL PRODUCTS. (R3-HYDROGEN.) THE FINAL PRODUCTS ARE ALSO USEFUL AS INTERMEDIATES FOR PREPARING PHARMACEUTICALLY ACTIVE COMPOUNDS, AND, MORE SPECIFICALLY, FOR PREPARING THE CORRESPONDING 2,N6-ETHENO-5&#39;&#39;-ADENOSINE CARBOXAMIDES.

p 3,830,795 Ice Patented Aug. 20, 19-74 3,830,795 LN -ETHENGS-ADENOSINECARBOXYLATES Raj Nandan Prasad, Pierrefonds, Quebec, and David LyonGarmaise, Montreal, Quebec, Canada, assignors to AbbottLaboratoriesyNorth Chicago, Ill. No Drawing. Filed Dec. 21, 1972, Ser.No. 317,325

Int; Cl. C07d 51/54 US. Cl. 260-211.5 R 3 Claims ABSTRACT OF THEDISCLOSURE Esters of l,N -etheno-5'-adenosine carboxylic acidrepresented by the formula a 4 N N wherein R is loweralkyl,loweralkenyl, loweralkynyl or cycloalkyl; and R and R each are hydrogenor acyl, or R and R taken together form an isopropylidene or benzylidenemoiety; and the pharmaceutically acceptable acid addition salts thereof.

The compounds wherein R and R are hydrogen are useful in treatingcardiovascular disorders and are particularly useful as anti-anginal andanti-hypertensive agents. Compounds wherein R and R are acyl or whentaken together form an isopropylidene or benzylidene moiety areintermediates useful in the preparation of the final products. (R and R=hydrogen.) The final products are also useful as intermediates forpreparing pharmaceutically active compounds, and, more specifically, forpreparing the corresponding 1,N -etheno-5'-adenosine carboxamides.

DETAILED DESCRIPTION OF THE INVENTION This invention relates to novelnucelosides, and more particularly relates to 1,N -etheno-5'-adenosinecarboxylates.

The compounds of this invention are represented by the formula areintermediates useful in the preparation of the final products. The finalproducts are also useful as intermediates for producing pharmaceuticallyactive compounds and more specifically, are useful in producing thecorresponding amides which are useful as anti'anginal andantihypertensive agents.

The term loweralkyl, as used herein, refers to both straight andbranched alkyl radicals containing from 1 to 6 carbon atoms, includingmethyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl,iso-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl and the like.

Loweralkenyl refers to the C to C alkyl groups, as defined above, fromwhich a hydrogen atom has been removed from each of two adjacent carbonatoms to produce ethylenic unsaturation; e.g., vinyl, allyl, methallyl,l-pentenyl and the like.

Loweralkynyl refers to the C to C alkyl groups as defined above, fromwhich 2 hydrogen atoms have been removed from each of two adjacentcarbon atoms to pro duce acetylenic unsaturation such as ethynyl,propargyl, Z-butynyl, l-pentynyl and the like.

The term cycloalkyl refers to C -C cycloalkyl groups, namely,cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term pharmaceutically acceptable acid addition salts refers tonon-toxic sats prepared by reacting the ester with the appropriateorganic or inorganic acid, or by utilizing an acid addition salt of theappropriate intermediate. Representative salts include thehydrochloride, hydrobromide, sulfate, bisulfate, acetate, valerate,oleate, laurate, borate, benzoate, lactate, phosphate, tosylate,citrate, maleate, succinate, tartrate, napsylate and the like.

The term acyl refers to acetyl, propionyl, bntyryl and the like.

The compounds of this invention are useful as antianginal agents atdosages of from 0.1 to mg./kg. of body Weight daily.

The anti-anginal activity was first established by measuring theincrease in coronary sinus partial pressure of oxygen (p0 according tothe method of Schoepke, et al., Pharmacologist 8; 204 (1966).

Generally speaking, the compounds of this invention are prepared byreacting adenosine-5'-carboxylic acid prepared from 2,3'-isopropylideneadenosine, according to the method described by Harmon et al., Chem.Ind. 1969, (1141) with an appropriate dry alcohol in the presence of anacid catalyst like thionylchloride to obtain the ester. The ester isthen reacted with chloroacetaldehyde according to the following reactionscheme to obtain the etheno compounds of this invention:

Reaction Scheme Q? .no on 5 OHH 3 The following examples furthervillustrate this invention:

EXAMPLE 1 Adenosine- '-Carboxylic Acid, Ethyl Ester 11.7 g. ofIsopropylidene adenosine were dissolved in 3.5 liters of water and thepH was adjusted to 12.2 by the addition of 5.85 g. of potassiumhydroxide. 23.7 g. of potassium permanganate in 825 ml. of water wereadded dropwise with stirring over a period of 3% hours. The solution wasthen allowed to sit at room temperature overnight. The excesspermanganate was destroyed by the dropwise addition of 30% hydrogenperoxide and the reaction mixture was filtered through a layer of NHwashed Celite. The yellow filtrate was concentrated in vacuo at 35-45 to600 ml. and the acid precipitated in an ice bath by adjusting the pH to4.5 by the dropwise addition of 1:3 HCl. The white precipitate waswashed with dilute (121000) acetic acid and dried at 135 C. to yield7.93 g. of the crude isopropylidene product, m.p. 265-8. The materialwas taken up in 100 ml. of dilute NH and recrystallized by adjusting thepH to 4.5 by the addition of 1:3 acetic acid to yield 7.7 g. of 2',3'-isopropylidene adenosine-5'-carboxylic acid, m.p. 2723.

Analysis Calcd. for C H N O C, 47.89; -H, 4.65; N, 21.59;

0, 25.03 Found: C, 48.60; H, 4.71; N, 21.80; 0, 24.90

EXAMPLE 2 'Ethyl 1,N -Etheno) Adenosine-5-Carboxylate MonohydrochlorideA suspension of ethyl adenosine-5-carboxylate (4.0 g.; 0.013 mole) inwater (70 ml.) containing chloroacetaldehyde (40 ml. of a 30% aqueoussolution) and a few drops of glacial acetic acid was stirred at 50 C.for 18 hours.

At the end of this period the reaction mixture was evaporated to drynessunder reduced pressure. The residue was recrystallized from absoluteethanol to give the analytically pure ethyl (l,N-etheno)adenosine-5-carboxylate monohydrochloride containing one mole ofethanol, melting at 128-30 dec.

R, 0.47 (solvent system: n-butanol/wate11=43/7). Anal.

Calcd. for C H N O HCL-EtOH; C, 46.21; H, 5.33;

N, 16.84 Found: C, 45.74; H, 5.22; N, 17.25

The ethyl adenosine-5'-carboxylate hydrochloride required was preparedby the following method:

A suspension of adenosine-5'-carboxylic acid (5.62 g.; 0.02 mole) inabsolute ethanol (300 ml.) was cooled and thionyl chloride (6.0 ml.) wasadded dropwise at l0 C. The reaction mixture was stirred for 16 hours atroom temperature. At the end of this period the mixture was cooled to-l0 C. and filtered. The residue was washed with cold absolute ethanoland ether to give 6.7 g. (97%) of ethyl adenosine-'-carboxylatehydrochloride as a white powder, melting at 171-72 dec. This sample waspure enough for further reaction.

Recrystallization from absolute ethanol gave the analytical samplemelting at 174 dec.; [u] 22 C. i0.55 (O=1.8 in H O). Anal. Calcd. for CH N O J-ICI (345.5); C, 41.67; H,

p 4.63; Cl, 10.27; N, 20.26

Found: C, 41.91; H, 4.91; Cl, 10.07; N, 19.81 The free base (ethyladenosine- '-carboxylate) was obtained by treating the aqueoussolution,v of the hydrochloride with a NaHCO solution at 5 C.

EXAMPLE 3 1,N-Etheno adenosine-5-carboxylic acid, allyl ester ispreparedv according to the method of Example 2 from adenosine-'-carboxylic acid, allyl ester and chloroacetaldehyde.

EXAMPLE 4 1,N -Etheno adenosine-5'-carboxylic acid, n-butyl ester isprepared according to the method of Example 2 from adenosine--carboxylic 'acid, n-butyl ester. L EXAMPLE-.5 1,N -Etheno adenosine-5-carboxylic iacid," ester is prepared according to themethod of Example2 from adenosine- -carboxylic-acid,, iso-propyl ester andchloroacetaldehyde. l E A PLE 6,

LN -EthenO adenosine-5"-carboxylic acid,-.[.propargyl ester is preparedaccording to the method of Example 2 from adenosine-5'-carboxylic acidpropargyl esterj 'and chloroacetaldehyde.

EXAMPLE 7 lN -Etheno adenosine- -carboxylic acid, n-pentyl ester isprepared according to'the method of Example 2 fromadenosine-5-carboxylic acid, n-pentyl ester and chloroacetaldehyde.

EXAMPLE 8 1,N -Etheno adenosine-5'-carboxylic acid, methallyl ester isprepared according to the method of Example 2 from adenosine--carboxylic. acid methallyl ester and chloroacetaldehyde.

EXAMPLE 9 1,N -Etheno adenosine-5'-carboxylic acid, -1-pentynyl ester isprepared according to the methodof Example 2 from adenosine-5-carboxylicacid, -l-pentynyl ester and chloroacetaldehyde. J Y; 1 1 EXAMPLE 10 1,N-Etheno adenosine- '-carboxylic acid,- cyclopentyl ester is preparedaccording to the method of Example 2 from adenosine-5-car-boxylic acid,cyclopentyl ester and chloroacetaldehyde. ,l EXAMPLE 11 Tabletscontaining 25 mg. of 1,N -Etheno adenosine- 5'-carboxylic acid andhaving the following composition are prepared according to methods well'known in the art.

Mg. 1,N -Etheno adenosine- -carboxylic acid, ethyl ester hydrochloride Yi Starch v I. 10 Colloidal silica p 1 I 3 Magnesium stearate 2 wherein Ris loweralkyl, loweralkenyl, loweralkynyl or a cycloalkyl of 3 to 6carbon atoms; and R and R each are hydrogen, acetyl, propionyl orbutyryl, or R and R taken together form an isopropylidene or benzilidenemoiety; and the pharmaceutically acceptable acid addition salts thereof.

2. A compound in accordance with Claim 1, 1,N etheno-5'-adenosinecarboxylic acid, ethyl ester, or a pharmaceutically acceptable acidaddition salt thereof.

3. A compound in accordance with Claim 2, LN- etheno-5-adenosinecarboxylic acid, ethyl ester hydrochloride.

6 References Cited UNITED STATES PATENTS 3,551,409 12/1970 Kampc et a1.260-2l1.5-R

5 3,697,504 10/1972 Schmidt 260-2115 R JOHNNIE R. BROWN, PrimaryExaminer US. Cl. X.R.

?UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent N 3, 830,795 Dated August 20, 1974 I td Raj Nandan Prasad and David Lyon GarmaiseIt is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

In Column 2, lines 60 71, please delete last compound of formula:

QM I

f 0 .HC

Sigma and sealed this--3rdday of December 1974.

(SEAL) Attest:

McCOY M. GIBSON JR. C. MARSHALL DANN Arresting Officer Commissioner ofPatents

